缺乏功能性 p53 的癌细胞预后较差，需要有效的治疗策略。抑制 G2/M 细胞周期检查点看门人 WEE1 是治疗 p53 缺陷型 NSCLC 的一种有前景的方法。在这里，我们阐明了 p53 和 WEE1 之间的联系，并探索了治疗 p53 缺陷型 NSCLC 的协同治疗方法。我们的研究表明，p53 缺陷通过抑制 WEE1 的 SUMO 化过程来上调 WEE1 的蛋白水平和激酶活性，从而增强 p53 缺陷的 NSCLC 对 WEE1 抑制剂的敏感性。此外，我们证明 WEE1 抑制剂 Adavosertib 会诱导细胞内脂质过氧化，特别是在 p53 缺陷的 NSCLC 细胞中，这表明与促氧化剂药物具有潜在的协同作用。重新利用双硫仑 (DSF) 是一种与铜 (Cu) 联合使用的酗酒治疗药物，具有抗 NSCLC 的促氧化特性。 DSF-Cu 处理的 p53 缺陷型 NSCLC 细胞显示 WEE1 蛋白水平呈时间依赖性增加。对 Adavosertib 和 DSF-Cu 联合疗法的后续评估显示，在 p53 缺陷细胞和异种移植模型中观察到细胞活力降低，肿瘤体积更小，肿瘤重量更轻，同时与溶质载体家族 7 成员 11 (SLC7A11) 相关)/谷胱甘肽调节的铁死亡途径激活。总之，我们的研究结果阐明了 p53 和 WEE1 之间的分子相互作用，并揭示了一种治疗 p53 缺陷型 NSCLC 的新型协同治疗策略。版权所有 © 2024。由 Elsevier B.V 出版。

Cancer cells lacking functional p53 exhibit poor prognosis, necessitating effective treatment strategies. Inhibiting WEE1, the G2/M cell cycle checkpoint gatekeeper, represents a promising approach for treating p53-deficient NSCLC. Here, we elucidate the connection between p53 and WEE1 and explore a synergistic therapeutic approach for managing p53-deficient NSCLC. Our study reveals that p53 deficiency upregulates both protein levels and kinase activity of WEE1 by inhibiting its SUMOylation process, thereby enhancing the susceptibility of p53-deficient NSCLC to WEE1 inhibitors. Furthermore, we demonstrate that the WEE1 inhibitor Adavosertib induces intracellular lipid peroxidation, specifically in p53-deficient NSCLC cells, suggesting potential synergy with pro-oxidant drugs. Repurposing Disulfiram (DSF), an alcoholism treatment drug used in combination with copper (Cu), exhibits pro-oxidant properties against NSCLC. DSF-Cu-treated p53-deficient NSCLC cells show a time-dependent increase in WEE1 protein levels. Subsequent evaluation of the combination therapy involving Adavosertib and DSF-Cu reveals reduced cell viability along with smaller tumor volumes and lighter tumor weights observed both in p53-deficient cells as well as in xenograft models while correlating with solute carrier family 7-member 11 (SLC7A11)/glutathione-regulated ferroptosis pathway activation. In conclusion, our findings elucidate the molecular interplay between p53 and WEE1 and unveil a novel synergistic therapeutic strategy for treating p53-deficient NSCLC.Copyright © 2024. Published by Elsevier B.V.